Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.

Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.

Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model.

Skeletal muscle is responsible for the majority of glucose disposal following meals, and this is achieved by insulin-mediated trafficking of glucose transporter type 4 (GLUT4) to the cell membrane. The eight-protein exocyst trafficking complex facilitates targeted docking of membrane-bound vesicles, a process underlying the regulated delivery of fuel transporters. We previously demonstrated the role of exocyst subunit EXOC5 in insulin-stimulated GLUT4 exocytosis and glucose uptake in cultured rat skeletal myoblasts. However, the in vivo role of EXOC5 in skeletal muscle remains unclear. Using mice with inducible, skeletal-muscle-specific knockout of exocyst subunit EXOC5 (Exoc5-SMKO), we examined how muscle-specific disruption of the exocyst would affect glucose homeostasis in vivo. We found that both male and female Exoc5-SMKO mice displayed elevated fasting glucose levels. Additionally, male Exoc5-SMKO mice had impaired glucose tolerance and lower serum insulin levels. Using indirect calorimetry, we observed that male Exoc5-SMKO mice have a reduced respiratory exchange ratio during the light period and lower energy expenditure. Using the hyperinsulinemic-euglycemic clamp method, we further showed that insulin-stimulated skeletal muscle glucose uptake is reduced in Exoc5-SMKO males compared with wild-type controls. Overall, our findings indicate that EXOC5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle and regulate glucose homeostasis in vivo.

Selenoprotein I (selenoi) as a critical enzyme in the central nervous system.

Selenoprotein I (selenoi) is a unique selenocysteine (Sec)-containing protein widely expressed throughout the body. Selenoi belongs to two different protein families: the selenoproteins that are characterized by a redox reactive Sec residue and the lipid phosphotransferases that contain the highly conserved cytidine diphosphate (CDP)-alcohol phosphotransferase motif. Selenoi catalyzes the third reaction of the CDP-ethanolamine branch of the Kennedy pathway within the endoplasmic reticulum membrane. This is not a redox reaction and does not directly involve the Sec residue, making selenoi quite distinct among selenoproteins. Selenoi is also unique among lipid phosphotransferases as the only family member containing a Sec residue near its C-terminus that serves an unknown function. The reaction catalyzed by selenoi involves the transfer of the ethanolamine phosphate group from CDP-ethanolamine to one of two lipid donors, 1,2-diacylglycerol (DAG) or 1-alkyl-2-acylglycerol (AAG), to produce PE or plasmanyl PE, respectively. Plasmanyl PE is subsequently converted to plasmenyl PE by plasmanylethanolamine desaturase. Both PE and plasmenyl PE are critical phospholipids in the central nervous system (CNS), as demonstrated through clinical studies involving SELENOI mutations as well as studies in cell lines and mice. Deletion of SELENOI in mice is embryonic lethal, while loss-of-function mutations in the human SELENOI gene have been found in rare cases leading to a form of hereditary spastic paraplegia (HSP). HSP is an upper motor disease characterized by spasticity of the lower limbs, which is often manifested with other symptoms such as impaired vision/hearing, ataxia, cognitive/intellectual impairment, and seizures. This article will summarize the current understanding of selenoi as a metabolic enzyme and discuss its role in the CNS physiology and pathophysiology.

Female Mice with Selenocysteine tRNA Deletion in Agrp Neurons Maintain Leptin Sensitivity and Resist Weight Gain While on a High-Fat Diet.

The role of the essential trace element selenium in hypothalamic physiology has begun to come to light over recent years. Selenium is used to synthesize a family of proteins participating in redox reactions called selenoproteins, which contain a selenocysteine residue in place of a cysteine. Past studies have shown that disrupted selenoprotein expression in the hypothalamus can adversely impact energy homeostasis. There is also evidence that selenium supports leptin signaling in the hypothalamus by maintaining proper redox balance. In this study, we generated mice with conditional knockout of the selenocysteine tRNA[Ser]Sec gene (Trsp) in an orexigenic cell population called agouti-related peptide (Agrp)-positive neurons. We found that female TrspAgrpKO mice gain less weight while on a high-fat diet, which occurs due to changes in adipose tissue activity. Female TrspAgrpKO mice also retained hypothalamic sensitivity to leptin administration. Male mice were unaffected, however, highlighting the sexually dimorphic influence of selenium on neurobiology and energy homeostasis. These findings provide novel insight into the role of selenoproteins within a small yet heavily influential population of hypothalamic neurons.

Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.

Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration. SIGNIFICANCE STATEMENT: Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.

Mice lacking selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures.

Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant defense. Among selenoproteins, selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple selenocysteine residues and has been postulated to act in selenium transport. Within the brain, Sepp1 delivers selenium to neurons by binding to the ApoER2 receptor. Upon feeding a selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function. Selenocysteine lyase (Scly) is an enzyme that plays an important role in selenium homeostasis, in that it catalyzes the decomposition of selenocysteine and allows selenium to be recycled for additional selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low selenium diet. To gain insight into the relationship between Sepp1 and Scly in selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly(-/-)Sepp1(-/-)) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1(-/-) mice, as these mice needed supraphysiological selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain selenoprotein function in the mammalian brain.

Deletion of selenoprotein M leads to obesity without cognitive deficits.

Selenium is an essential trace element that is co-translationally incorporated into selenoproteins in the form of the 21st amino acid, selenocysteine. This class of proteins largely functions in oxidation-reduction reactions and is critically involved in maintaining proper redox balance essential to health. Selenoprotein M (SelM) is a thioredoxin-like endoplasmic reticulum-resident protein that is highly expressed in the brain and possesses neuroprotective properties. In this study, we first assessed the regional pattern of SelM expression in the mouse brain to provide insights into the potential functional implications of this protein in physiology and behavior. Next, we generated transgenic mice with a targeted deletion of the SelM gene and subjected them to a battery of neurobehavioral tests to evaluate motor coordination, locomotion, and cognitive function in comparison with wild-type controls. Finally, these mice were tested for several measures of metabolic function and body composition. Our results show that SelM knock-out (KO) mice display no deficits in measures of motor coordination and cognitive function but exhibit increased weight gain, elevated white adipose tissue deposition, and diminished hypothalamic leptin sensitivity. These findings suggest that SelM plays an important role in the regulation of body weight and energy metabolism.

Selenium Protects Mouse Hypothalamic Cells from Glucocorticoid-Induced Endoplasmic Reticulum Stress Vulnerability and Insulin Signaling Impairment.

The use of glucocorticoid medications is known to cause metabolic side effects such as overeating, excess weight gain, and insulin resistance. The hypothalamus, a central regulator of feeding behavior and energy expenditure, is highly responsive to glucocorticoids, and it has been proposed that it plays a role in glucocorticoid-induced metabolic defects. Glucocorticoids can alter the expression and activity of antioxidant enzymes and promote the accumulation of reactive oxygen species. Recent evidence indicates that selenium can counter the effects of glucocorticoids, and selenium is critical for proper hypothalamic function. This study sought to determine whether selenium is capable of protecting hypothalamic cells from dysfunction caused by glucocorticoid exposure. We treated mHypoE-44 mouse hypothalamic cells with corticosterone to study the effects on cellular physiology and the involvement of selenium. We found that corticosterone administration rendered cells more vulnerable to endoplasmic reticulum stress and the subsequent impairment of insulin signaling. Supplementing the cell culture media with additional selenium alleviated endoplasmic reticulum stress and promoted insulin signaling. These findings implicate a protective role of selenium against chronic glucocorticoid-induced hypothalamic dysfunction.

Selenoprotein I deficiency in T cells promotes differentiation into tolerant phenotypes while decreasing Th17 pathology.

Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase contributing to cellular metabolism and the synthesis of glycosylphosphatidylinositol (GPI) anchors. SELENOI knockout (KO) in T cells has been shown to impair metabolic reprogramming during T cell activation and reduce GPI-anchored Thy-1 levels, which are both crucial for Th17 differentiation. This suggests SELENOI may be important for Th17 differentiation, and we found that SELENOI was indeed up-regulated early during the activation of naïve CD4+ T cells in Th17 conditions. SELENOI KO reduced RORγt mRNA levels by decreasing SOX5 and STAT3 binding to promoter and enhancer regions in the RORC gene encoding this master regulator of Th17 cell differentiation. Differentiation of naïve CD4+ T cells into inflammatory versus tolerogenic Th cell subsets was analyzed and results showed that SELENOI deficiency skewed differentiation away from pathogenic Th17 cells (RORγt+ and IL-17A+ ) while promoting tolerogenic phenotypes (Foxp3+ and IL-10+ ). Wild-type and T cell-specific SELENOI KO mice were subjected to experimental autoimmune encephalitis (EAE), with KO mice exhibiting diminished clinical symptoms, reduced CNS pathology and decreased T cell infiltration. Flow cytometry showed that SELENOI T cell KO mice exhibited lower CD4+ RORγt+ and CD4+ IL-17A+ T cells and higher CD4+ CD25+ FoxP3+ T cells in CNS tissues of mice subjected to EAE. Thus, the metabolic enzyme SELENOI is up-regulated to promote RORγt transcription that drives Th17 differentiation, and SELENOI deficiency shifts differentiation toward tolerogenic phenotypes while protecting against pathogenic Th17 responses.

The central amygdala nucleus via corticotropin-releasing factor is necessary for time-limited consolidation processing but not storage of contextual fear memory.

The central nucleus of the amygdala (CeA) is traditionally portrayed in fear conditioning as the key neural output that relays conditioned information established in the basolateral amygdala complex to extra-amygdalar brain structures that generate emotional responses. However, several recent studies have questioned this serial processing view of the amygdalar fear conditioning circuit by showing an influence of the CeA on memory consolidation. We previously reported that inhibition of endogenous CeA secretion of corticotropin-releasing factor (CRF) at the time of contextual training effectively impaired fear memory consolidation. However, the time-dependent range of CeA CRF secretion in facilitating consolidation processing has not been examined. Therefore, to address this issue, we performed CeA site-specific microinjections of CRF antisense oligonucleotides (CRF ASO) at several post-training time intervals. Rats microinjected with CRF ASO at post-training intervals up to 24-h subsequently exhibited significant impairments in contextual freezing retention in contrast to animals treated 96-h after training. To further establish the validity of the results, CeA fiber-sparing lesions were made at two distinct post-training periods (24-h and 96-h), corresponding respectively to the temporal intervals when CeA CRF ASO administration disrupted or had no significant effects on memory consolidation. Similar to the CeA CRF ASO results, CeA lesions made 24-h, but not 96-h, after training induced significant freezing deficits in the retention test. In conclusion, the current results demonstrate: (1) an extended involvement of CeA CRF in contextual memory consolidation and (2) that contextual fear memory storage is not dependent on a functional CeA.

Pericytic porters: helping leptin step in.

A new mechanism of leptin extravasation from the bloodstream into the brain may have been discovered. According to recent findings by Butiaeva et al., pericytes within the blood-brain barrier (BBB) express the leptin receptor and, upon activation, facilitate the movement of the appetite-suppressing hormone into deeper regions of the hypothalamus.

Selenoprotein M Promotes Hypothalamic Leptin Signaling and Thioredoxin Antioxidant Activity.

Aims: Selenoproteins are an essential class of proteins involved in redox signaling and energy metabolism. However, the functions of many selenoproteins are not clearly established. Selenoprotein M (SELENOM), an endoplasmic reticulum (ER)-resident oxidoreductase bearing structural similarity to thioredoxin (TXN), is among those yet to be fully characterized. This protein is highly expressed in hypothalamic regions involved in leptin signaling and has been previously linked to energy metabolism. Herein, we performed a series of studies using in vivo and in vitro models to probe the specific influence of SELENOM on hypothalamic leptin signaling and assess SELENOM-regulated pathways. Innovation and Results: Our initial experiment in vivo demonstrated that (i) leptin promotes hypothalamic expression of SELENOM and (ii) leptin-induced STAT3 phosphorylation is impeded by SELENOM deficiency. Additional in vitro studies using mHypoE-44 immortalized hypothalamic neurons corroborated these findings, as SELENOM deficiency obstructed downstream STAT3 phosphorylation and cytosolic calcium responses evoked by leptin treatment. Correspondingly, SELENOM overexpression enhanced leptin sensitivity. Microarray analysis conducted in parallel on hypothalamic tissue and mHypoE-44 cells revealed multiple genes significantly affected by SELENOM deficiency, including thioredoxin interacting protein, a negative regulator of the TXN system. Further analysis determined that (i) SELENOM itself possesses intrinsic TXN activity and (ii) SELENOM deficiency leads to a reduction in overall TXN activity. Finally, mHypoE-44 cells lacking SELENOM displayed diminished activation of the nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) signaling pathway and increased susceptibility to ER stress-mediated cell death. Conclusion: In sum, these findings establish SELENOM as a positive regulator of leptin signaling and TXN antioxidant activity in the hypothalamus. Antioxid. Redox Signal. 35, 775-787.

Juvenile Selenium Deficiency Impairs Cognition, Sensorimotor Gating, and Energy Homeostasis in Mice.

Selenium (Se) is an essential micronutrient of critical importance to mammalian life. Its biological effects are primarily mediated via co-translational incorporation into selenoproteins, as the unique amino acid, selenocysteine. These proteins play fundamental roles in redox signaling and includes the glutathione peroxidases and thioredoxin reductases. Environmental distribution of Se varies considerably worldwide, with concomitant effects on Se status in humans and animals. Dietary Se intake within a narrow range optimizes the activity of Se-dependent antioxidant enzymes, whereas both Se-deficiency and Se-excess can adversely impact health. Se-deficiency affects a significant proportion of the world's population, with hypothyroidism, cardiomyopathy, reduced immunity, and impaired cognition being common symptoms. Although relatively less prevalent, Se-excess can also have detrimental consequences and has been implicated in promoting both metabolic and neurodegenerative disease in humans. Herein, we sought to comprehensively assess the developmental effects of both Se-deficiency and Se-excess on a battery of neurobehavioral and metabolic tests in mice. Se-deficiency elicited deficits in cognition, altered sensorimotor gating, and increased adiposity, while Se-excess was surprisingly beneficial.

The central nucleus of the amygdala and corticotropin-releasing factor: insights into contextual fear memory.

The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA before contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately before retention testing did not impair freezing, suggesting that the previously observed retention deficits were caused by inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator.

Deficits in Glutamic Acid Decarboxylase 67 Immunoreactivity, Parvalbumin Interneurons, and Perineuronal Nets in the Inferior Colliculus of Subjects With Schizophrenia.

Aberrant processing of auditory stimuli is a prominent feature of schizophrenia (SZ). Prior studies have chronicled histological abnormalities in the auditory cortex of SZ subjects, but whether deficits exist at upstream, subcortical levels has yet to be established. En route to the auditory cortex, ascending information is integrated in the inferior colliculus (IC), a highly gamma amino butyric acid (GABA) ergic midbrain structure that is critically involved in auditory processing. The IC contains a dense population of parvalbumin-immunoreactive interneurons (PVIs), a cell type characterized by increased metabolic demands and enhanced vulnerability to oxidative stress. During development, PVIs are preferentially surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures that promote redox homeostasis and excitatory/inhibitory balance. Moreover, in SZ, deficits in PVIs, PNNs, and the GABA synthesizing enzyme, glutamic acid decarboxylase (Gad67), have been extensively documented in cortical regions. Yet, whether similar impairments exist in the IC is currently unknown. Thus, we compared IC samples of age- and sex-matched pairs of SZ and unaffected control subjects. SZ subjects exhibited lower levels of Gad67 immunoreactivity and a decreased density of PVIs and PNNs within the IC. These findings provide the first histological evidence of IC GABAergic abnormalities in SZ and suggest that SZ-related auditory dysfunction may stem, in part, from altered IC inhibitory tone.

Cell-Type Specific Analysis of Selenium-Related Genes in Brain.

Selenoproteins are a unique class of proteins that play key roles in redox signaling in the brain. This unique organ is comprised of a wide variety of cell types that includes excitatory neurons, inhibitory neurons, astrocytes, microglia, and oligodendrocytes. Whereas selenoproteins are known to be required for neural development and function, the cell-type specific expression of selenoproteins and selenium-related machinery has yet to be systematically investigated. Due to advances in sequencing technology and investment from the National Institutes of Health (NIH)-sponsored BRAIN initiative, RNA sequencing (RNAseq) data from thousands of cortical neurons can now be freely accessed and searched using the online RNAseq data navigator at the Allen Brain Atlas. Hence, we utilized this newly developed tool to perform a comprehensive analysis of the cell-type specific expression of selenium-related genes in brain. Select proteins of interest were further verified by means of multi-label immunofluorescent labeling of mouse brain sections. Of potential significance to neural selenium homeostasis, we report co-expression of selenoprotein P (SELENOP) and selenium binding protein 1 (SELENBP1) within astrocytes. These findings raise the intriguing possibility that SELENBP1 may negatively regulate astrocytic SELENOP synthesis and thereby limit downstream Se supply to neurons.

Agrp-Specific Ablation of Scly Protects against Diet-Induced Obesity and Leptin Resistance.

Selenium, an essential trace element known mainly for its antioxidant properties, is critical for proper brain function and regulation of energy metabolism. Whole-body knockout of the selenium recycling enzyme, selenocysteine lyase (Scly), increases susceptibility to metabolic syndrome and diet-induced obesity in mice. Scly knockout mice also have decreased selenoprotein expression levels in the hypothalamus, a key regulator of energy homeostasis. This study investigated the role of selenium in whole-body metabolism regulation using a mouse model with hypothalamic knockout of Scly. Agouti-related peptide (Agrp) promoter-driven Scly knockout resulted in reduced weight gain and adiposity while on a high-fat diet (HFD). Scly-Agrp knockout mice had reduced Agrp expression in the hypothalamus, as measured by Western blot and immunohistochemistry (IHC). IHC also revealed that while control mice developed HFD-induced leptin resistance in the arcuate nucleus, Scly-Agrp knockout mice maintained leptin sensitivity. Brown adipose tissue from Scly-Agrp knockout mice had reduced lipid deposition and increased expression of the thermogenic marker uncoupled protein-1. This study sheds light on the important role of selenium utilization in energy homeostasis, provides new information on the interplay between the central nervous system and whole-body metabolism, and may help identify key targets of interest for therapeutic treatment of metabolic disorders.

Barnes Maze Procedure for Spatial Learning and Memory in Mice.

The Barnes maze is a dry-land based rodent behavioral paradigm for assessing spatial learning and memory that was originally developed by its namesake, Carol Barnes. It represents a well-established alternative to the more popular Morris Water maze and offers the advantage of being free from the potentially confounding influence of swimming behavior. Herein, the Barnes maze experimental setup and corresponding procedures for testing and analysis in mice are described in detail.

Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis.

The human selenoprotein family contains 25 members that share the common feature of containing the amino acid, selenocysteine (Sec). Seven selenoproteins are localized to the endoplasmic reticulum (ER) and exhibit different structural features contributing to a range of cellular functions. Some of these functions are either directly or indirectly related to calcium (Ca2+) flux or homeostasis. The presence of the unique Sec residue within these proteins allows some to exert oxidoreductase activity, while the function of the Sec in other ER selenoproteins remains unclear. Some functional insight has been achieved by identifying domains within the ER selenoproteins or through the identification of binding partners. For example, selenoproteins K and N (SELENOK AND SELENON) have been characterized through interactions detected with the inositol 1,4,5-triphosphate receptors (IP3Rs) and the SERCA2b pump, respectively. Others have been linked to chaperone functions related to ER stress or Ca2+ homeostasis. This review summarizes the details gathered to date regarding the ER-resident selenoproteins and their effect on Ca2+ regulated pathways and outcomes in cells.

Hypothalamic redox balance and leptin signaling - Emerging role of selenoproteins.

The hypothalamus is the central neural site governing food intake and energy expenditure. During the past 25 years, understanding of the hypothalamic cell types, hormones, and circuitry involved in the regulation of energy metabolism has dramatically increased. It is now well established that the adipocyte-derived hormone, leptin, acts upon two distinct groups of hypothalamic neurons that comprise opposing arms of the central melanocortin system. These two cell populations are anorexigenic neurons expressing proopiomelanocortin (POMC) and orexigenic neurons that express agouti-related peptide (AGRP). Several important studies have demonstrated that reactive oxygen species and endoplasmic reticulum stress significantly impact these hypothalamic neuronal populations that regulate global energy metabolism. Reactive oxygen species and redox homeostasis are influenced by selenoproteins, an essential class of proteins that incorporate selenium co-translationally in the form of the 21st amino acid, selenocysteine. Levels of these proteins are regulated by dietary selenium intake and they are widely expressed in the brain. Of additional relevance, selenium supplementation has been linked to metabolic alterations in both animal and human studies. Recent evidence also indicates that hypothalamic selenoproteins are significant modulators of energy metabolism in both neurons and tanycytes, a population of glial-like cells lining the floor of the 3rd ventricle within the hypothalamus. This review article will summarize current understanding of the regulatory influence of redox status on hypothalamic nutrient sensing and highlight recent work revealing the importance of selenoproteins in the hypothalamus.